Transcript 16 MS 341final2014-08-23 10:472.3 MB

Demyelinating Diseases
DR. Abdulkader Daif, MD
Consultant and Professor of
Neurology
KKUH, Faculty of medicine
Group 341-2014
Introduction to
Multiple Sclerosis (MS)
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Chronic autoimmune disease
Progressive disease
Involves Immune System & Neurological System
Multifocal areas of demyelination
Disrupts ability of the nerve to conduct electrical
impulses
• Leads to symptoms
Classification of the Demyelinating diseases:
Multiple sclerosis:
A- Chronic relapsing encephalomyelopathic form.
B- Acute multiple sclerosis.
C- Neuromyelitis optica.
Diffuse cerebral sclerosis (encephalitis periaxalis diffuse) or Schilder and concentric
sclerosis of Balo.
Acute disseminated encephalomyelitis.
A- Following measles, rubella & influenza.
B- Following rabies or smallpox vaccination.
Acute and subacute necrotizing hemorrhagic encephalitis.
A- Acute encephalopathic form (hemorrhagic leukoencephalitis of Hurst)
B- Subacute necrotic myelopathy
C- Acute brain purpura(acute pericapillary encephalorrhagia)
Types of MS
• Relapsing-remitting MS (RRMS)
▫ Affects 85% of newly diagnosed
▫ Attacks followed by partial or complete recovery
▫ Symptoms may be inactive for months or years
• Secondary-progressive MS (SPMS)
▫ Occasional relapses but symptoms remain constant,
no remission
▫ Progressive disability late in disease course
Types of MS
• Primary-progressive MS (PPMS)
– Affects approximately 10% of MS
population
– Slow onset but continuous worsening
condition
Multiple Sclerosis Subtypes
(Coyle P, CNS News 2002; adapted from Lublin F, et al Neurology 1996)
Epidemiology of MS
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Age onset 20 – 50 years old
Women are 2 times more likely to develop MS
500,000 cases in US
Over 2.5 million people around the world
More prevalent whites of northern European
ancestry
Multiple Sclerosis
An Immunogenetic Disease
Environmental Factors
Demographics/Epidemics
Microbial Agents
EBV
Vitamin D
Genetic Predisposition
• Twins studies
• HLA-DR2 (DRß1*1501)
(antigen presentation)
• IL-2Ra
• (regulatory T-cells)
• IL-7Ra
 (memory T-cells)
• ST8SIA1
Immune Dysregulation
Graphic courtesy of Dr. Suhayl Dhib-Jalbut.
MS
1. Research into the Causes of MS
Environmental
factors
Genetic
factors
MS
Immunological
factors
Other Factors
Influencing MS
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Vitamin D deficiency
▫ Vitamin D3 receptor important in immune function
▫ Present on T regulator cells
Infectious Mono/EBV
▫ 99% of MS patients have EBV titers
▫ Usually higher than in HC
▫ Pseudo follicles in meninges containing B cells showing ENA antigen
▫ EBER RNA found in inflammatory lesions
▫ Protein stimulates Toll 3 receptors which release proinflammatory interferons
▫ In inflammatory lesions T cells found surrounding B cells containing ENA
antigen
Genetics
▫ HLA DRB2 *1503 allele 2x risk factor
▫ IL 2 receptor
▫ IL 7 receptor
▫ 50 new candidates genes each with low risk factors
Symptoms of MS
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Vision problems
Numbness
Difficulty walking
Fatigue
Depression
Emotional changes
Vertigo & dizziness
Sexual dysfunction
• Coordination
problems
• Balance problems
• Pain
• Changes in cognitive
function
• Bowel/bladder
dysfunction
• Spasticity
Pathogenesis of MS
Multiple Sclerosis
Pathophysiology
• Disease process consists of loss of myelin,
disappearance of oligodendrocytes, and
proliferation of astrocytes
• Changes result in plaque formation with
plaques scattered throughout the CNS
Multiple Sclerosis
Pathophysiology
• Initially the myelin sheaths of the neurons in the
brain and spinal cord are attacked, but the nerve
fiber is not affected
• Patient may complain of noticeable impairment
of function
• Myelin can regenerate, and symptoms
disappear, resulting in a remission
Multiple Sclerosis
Etiology and Pathophysiology
• Myelin can be replaced by glial scar tissue
• Without myelin, nerve impulses slow down
• With destruction of axons, impulses are
totally blocked
• Results in permanent loss of nerve function
MS Disease Timeline
(Fox RJ, Sweeny PJ, Cleveland Clinic, May 2002)
Natural History of MS
Clinical and MRI Measures
Relapses/Disability
MRI Activity
Disability
MRI T2 Burden of Disease
Axonal Loss
Preclinical
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Secondary Progressive
MS
Relapsing-Remitting
MS
CIS
Time
Trapp BD, et al. Neuroscientist. 1999;5:48-57. Reprinted with permission from Sage Publications.
RECENT LESIONS
LATER
•Relatively acellular
•Myelin destruction
•Relative axon sparing
•Perivenous infiltration with MNP
•Breakdown of BBB
OLD LESION
Astrocyte
proliferation
•More clearly demarcated.
•Bare axons are
surrounded by astrocytes.
The Biology of MS
How does the CNS work?
Nerve Cell
Myelin surrounds the nerve fibers, protecting
them like the coating of a wire1
Myelin
Nerve fibers (or axon)
Cell body
Nerve fibers (or axon)
Myelin
Messages travel to and from the CNS through nerve cells3
The Biology of MS
How does MS affect the CNS?
Nerve Cell
Areas where myelin has been
damaged interrupt communication
Exposed nerve fibers are severed,
causing permanent damage
In MS, cells of the immune system attack myelin and can cause
permanent damage
How could autoimmune responses cause MS?
Inflammation and Axonal Transection
Disease
Stage
Main
Component
Main
Clinical
Outcome
Early
Inflammation and demyelination
Relapses
Late
Atrophy, axonal loss, and
increasing tissue destruction
(less Gd-defined inflammation,
demyelination ongoing)
Disability
The Biology
of MS
How is MS monitored?
MRI showing no signs
of damage
MRI showing an active
lesion*
MRI showing
permanent damage
Active
lesion
Permanent
damage
 These images may also help detect “silent” damage (lesions detected by MRI that do not
result in symptoms)1
 The impact of this damage depends on the destructiveness of the lesion and where it
is located
*The exact relationship between MRI findings and the clinical status of patients is unknown.
Magnetic Resonance Imaging (MRI) detects areas of inflammation
(active lesions) and areas of permanent damage in the brain1
Diagnosis of MS
• Clinically definite MS must meet criteria for1
▫ Dissemination in space
▫ Dissemination in time
• A single episode of MS-like symptoms (clinically isolated
syndrome [CIS]) will not meet these criteria
▫ But if MS is likely based on MRI, it still should be treated like MS
 Delaying treatment may be missing an important window of
opportunity to delay the onset of irreversible disability
▫ Requires close monitoring over time to confirm diagnosis
1. Polman CH, et al. Ann Neurol. 2005;58:840-846.
Revised McDonald Criteria for
Dissemination in Time
• At least 1 of the following
▫ A 2nd clinical episode
▫ A Gd-enhancing lesion detected ≥3 months after onset of initial
clinical event
 Located at a site different from the one corresponding to the initial
event
▫ A new T2 lesion detected any time after a reference scan that was
performed at least 30 days after the onset of an initial clinical
event
• Thus, it is not always necessary to wait for 2 attacks to
diagnose MS. A first attack plus changes on MRI may be
enough
Polman CH, et al. Ann Neurol. 2005;58:840-846.
Revised McDonald Criteria for
Dissemination in Space
• At least 3 of the following:
▫ ≥1 Gd-enhancing brain or spinal cord lesion or ≥9
T2 hyperintense brain and/or spinal cord lesions
of ≥3 mm in size if none of the lesions are Gdenhancing
▫ ≥1 brain infratentorial lesion or spinal cord lesion
≥3 mm in size
▫ ≥1 juxtacortical lesion ≥3 mm in size
▫ ≥3 periventricular lesions ≥3 mm in size
Polman CH, et al. Ann Neurol. 2005;58:840-846.
Clinical Features Suggestive of MS
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Onset between 15-50 years
Blurred or double vision
Lhermitte’s sign
Fatigue
Heat sensitivity
Bladder symptoms
Cognitive or affective changes
Clinical Features
Sensory Symptoms
• Numbness
& Paraesthesia
• Impaired vibration & Joint position sensation
• Lhermitte’s Sign ( Shock-like sensation in
the limb)
•Dysaesthesia + Sensory loss to pain & Temp.
Clinically Isolated Syndromes
Clinically Isolated Syndromes
• Transverse Myelitis
▫ Risk factors for MS
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Incomplete transverse myelitis
Asymmetric motor or sensory findings
Brain MRI lesions
Abnormal CSF
Abnormal VER and SSEPs
• Others (Brainstem, Cerebellum)
Optic Neuritis: Clinical Features
•Inflammatory demyelination of one or both optic nerves
• Pain around one eye
• Blurred vision
• Loss of color vision
• Swollen optic disc( Papillitis)
• Visual field defect
• Diplopia & Vertigo
Clinically Isolated Syndromes
• Optic Neuritis
▫ Risk factors for MS (60-75%)
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History of minor neurologic sxs
Unilateral optic neuritis
Brain MRI lesions
Abnormal CSF
Abormal VERs
Diseases to rule out
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Viral infections
Lyme disease
B12 deficiency
CVA
Lupus
Rheumatoid arthritis
Other connective
tissue disorders
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Vasculitis
Syphilis
Tuberculosis
Neurobrucellocis
HIV
Sarcoidosis
Neuro-Imaging and MS
Typical MRI Lesions in MS
Infratentorial
C and D: Courtesy of Daniel Pelletier, MD.
Juxtacortical
Typical MRI Lesions in MS
Periventricular
E: Courtesy of Daniel Pelletier, MD.
F: Courtesy of Tracy M. DeAngelis, MD.
Spinal Cord
Typical MRI Lesions in MS
Gd-enhancing
A and B: Courtesy of Tracy M. DeAngelis, MD.
Corpus Callosum
Distinguishing NMO from MS
NMO
Courtesy of Bruce A.C. Cree, MD, PhD, MCR
MS
Courtesy of Tracy M. DeAngelis, MD
Other Diagnostic Tools for MS
Visual Evoked Potentials (VEPs)
• Provides evidence of a lesion associated with
visual pathways
• Positive if shows delayed but well-preserved
wave forms
▫ Abnormal VEP is not specific for MS
• Can help establish dissemination in space
LABORATORY ASSISTED DIAGNOSIS
MS lesions in various stages can now be seen on
MRI
Cerebrospinal fluid analysis can identify
immunoglobulin synthesis
Evoked potentials can demonstrate clinically and
even MRI silent lesions
Other Diagnostic Tools for MS
CSF Analysis
• Positive if oligoclonal IgG bands present but absent from
corresponding serum sample or IgG index is elevated
▫ Sensitive but not specific: other causes of CNS inflammation can
yield similar findings
• Lymphocytic pleocytosis is rarely >50/mm3
• Protein levels rarely exceed 100 mg/dL
• Elevated myelin basic protein is not pathognomonic for
MS
Neurophysiological Investigations
No diagnostic test. Only support the clinical suspicion.
•Visual evoked potential(VEP): in optic nerve the latency of the large positive wave is delayed . the
amplitude may also be reduced.
•Somatosensory evoked response (SSEP) may detect central sensory pathway
lesion.
•Brain stem auditory evoked potential (BAEP) may detect brain
stem lesion.
Therapeutic Goals in MS
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Prevent disability
Prevent relapses
Relieve symptoms
Maintain well-being
Optimize quality of life
An effective therapy administered early in the
disease course can impact all of these goals
Existing Therapies and
Emerging Therapies for MS
2005
2006
2007
2010
2011
2012
2013
Orals
Injectables
BG 12 Oral
Fumarate
Oral
Cladribine
Rebif
Teriflunomide
Betaseron
FTY 720
Laquinimod
Copaxone
Fampridine
SB683699
ambulation indication?
Avonex
IV
IV Novantrone
Tysabri
Campath
Rituximab
II - RRMS; III - PPMS
Generic
Mitoxantrone
(oncology)
Daclizumab
(MS)
MBP 8298
approved
In phase II
In phase III
Filed
MLN1202
Second Second-Line MS Therapies
• Mitoxantrone
• Natalizumab
• Generally indicated for persons with suboptimal
response to first-line agents
• Require intravenous infusion
• Associated with life-threatening
adverse events
Oral MS Therapies
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Fingolimod
Fumarate
Teriflunomide
Laquinimod
Cladribine